4.3 Genetic Disorders
What is a genetic condition?
A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. Genetic disorders can be caused by a mutation in one gene (monogenic disorder), by mutations in multiple genes (multifactorial inheritance disorder), by a combination of gene mutations and environmental factors, or by damage to chromosomes (changes in the number or structure of entire chromosomes, the structures that carry genes).
As we unlock the secrets of the human genome (the complete set of human genes), we are learning that nearly all diseases have a genetic component. Some diseases are caused by mutations that are inherited from the parents and are present in an individual at birth, like sickle cell disease. Other diseases are caused by acquired mutations in a gene or group of genes that occur during a person’s life. Such mutations are not inherited from a parent, but occur either randomly or due to some environmental exposure (such as cigarette smoke). These include many cancers, as well as some forms of neurofibromatosis.
Genetic conditions can be grouped into four main categories:
1. Single gene conditions: caused by changes to one gene, often with simple and predictable inheritance patterns.
As discussed in unit 2, different patterns of inheritance exist:
- Dominant conditions occur when a person has one unaffected copy and one mutated copy of the gene. For example, Huntington’s disease.
- Recessive conditions only occur when an individual has two mutated copies of the gene. If a person has only one copy of the mutated gene, they are a carrier of the condition and may pass it to their children. For example, cystic fibrosis.
- X-linked conditions are caused by genes altered on the X chromosome – people with XY chromosomes are missing lots of genes encoded by the X, so will develop the condition if they have an altered gene on the X. For example, muscular dystrophy.
2. Chromosome conditions result from changes in the number or structure of the chromosomes.
- For example, Downs syndrome results from an extra chromosome 21. It’s also called trisomy 21, referring to three copies of chromosome 21
3. Multifactorial conditions (or complex diseases) are caused by changes in multiple genes, often in a complex interaction with environmental factors.
- Many types of cancer are caused in this way. For example, certain genetic mutations can put a person at higher risk of bowel cancer. This, combined with external factors like cigarette smoke or certain foods can make a person more likely to develop the disease.
4. Mitochondrial Disorders are caused by defects in the mitochondria (NINDS, 2024).
- They can affect one part of the body or many parts, including the brain, muscles, kidneys, heart, eyes, and ears. In most cases, mitochondrial disorders affect more than one type of cell, tissue, or organ.
We will explore these four types of conditions in the following chapters.
How are genetic conditions and genes named?
Naming genetic conditions
Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a new, previously unknown disorder are often the first to propose a name for the condition. Later, healthcare professionals, researchers, people affected by the condition, and other interested individuals may come together to revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately improve care and help researchers find new approaches to treatment.
Condition names are often derived from one or a combination of sources:
- The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency);
- The gene in which the variant (or mutation) that causes the condition occurs (for example,TUBB4A-related leukodystrophy);
- One or more major signs or symptoms of the disorder (for example, hypermanganesemia with dystonia, polycythemia vera, and cryptogenic cirrhosis);
- The parts of the body affected by the condition (for example, brain-lung-thyroid syndrome);
- The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan);
- A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea); or
- The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis is often called Lou Gehrig disease after the famous baseball player who was diagnosed with the condition).
Conditions named after a specific person are called eponyms. They can be in the possessive form (e.g., Alzheimer’s disease) or in the nonpossessive form (e.g., Down syndrome).
Naming genes
The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. The HGNC is a nonprofit organization funded by the U.S. National Human Genome Research Institute and the UK’s Wellcome Trust. The Committee has named more than 19,000 of the estimated 20,000 to 25,000 protein-coding genes in the human genome.
During the research process, genes often acquire several alternate names and symbols from researchers investigating the same gene. To resolve this confusion, the HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature.
A note on genetic nomenclature in relation to variants
Many genes are first identified in variant screens and, so, they tend to be named after their variant phenotypes — not the normal function or phenotype. This can cause some confusion for students of genetics. For example, there is an X-linked gene named white in fruit flies. Null variants of the white gene have white eyes, but the normal white+ allele has red eyes. This tells us that the wild type (normal) function of this gene is required to make red eyes. We now know its product is a protein that imports a colourless pigment precursor into developing cells of the eye. Why don’t we call it the “red” gene, since that is what its product does? Because there are more than one-dozen genes that, when mutant, alter the eye colour: violet, cinnabar, brown, scarlet, etc. For all of these genes, their function is also needed to make the eye wild-type red, and not the mutant colour. If we used the name “red” for all these genes, it would be confusing. So we use the distinctive mutant phenotype as the gene name. However, this can be problematic, as with the “lethal” variants described above. This problem is usually handled by giving numbers or locations to the gene name, or making up names that describe how they die (e.g., even-skipped, hunchback, hairy, runt, etc.).
What does it mean to have a genetic predisposition to a disease?
A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person’s genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family.
Genetic variations can have large or small effects on the likelihood of developing a particular disease. For example, certain variants (also called mutations) in the BRCA1 or BRCA2 genes greatly increase a person’s risk of developing breast cancer and ovarian cancer. Particular variations in other genes, such as BARD1 and BRIP1, appear to have a much smaller impact on a person’s breast cancer risk.
Current research is focused on identifying genetic changes that have a small effect on disease risk but are common in the general population. Although each of these variations only slightly increases a person’s risk, having changes in several different genes may combine to increase disease risk significantly. Changes in many genes, each with a small effect, may underlie susceptibility to many common diseases, including cancer, obesity, diabetes, heart disease, and mental illness. Researchers are working to calculate an individual’s estimated risk for developing a common disease based on the combination of variants in many genes across their genome. This measure, known as the polygenic risk score, is expected to help guide healthcare decisions in the future.
In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to an identified genetic change. These include other genetic factors (sometimes called modifiers) as well as lifestyle and environmental factors. Diseases that are caused by a combination of factors are described as multifactorial. Although a person’s genetic makeup cannot be altered, some lifestyle and environmental modifications (such as having more frequent disease screenings and maintaining a healthy weight) may be able to reduce disease risk in people with a genetic predisposition.
Modifiable and non-modifiable risk factors
Traditional risk factors for health outcomes, such as age, sex, and genetic inheritance (non-modifiable) and diet, physical activity, and smoking (modifiable), are paralleled by social and environmental factors that impact the epigenome, such as experiencing racism or living near industrial pollution. This illustrates how gene expression and, consequently, disease risk can be altered throughout an individual’s life.
Family health history is a non-modifiable risk factor—or is it?
“I met three different women who had been tested [genetic testing for mutations in the BReast CAncer susceptibility (BRCA) genes] early on, in 1996, when the BRCA test first came out. They told me their family history story of mothers, aunts, uncles, and a dad who suffered from breast or ovarian or related cancers, and it was heartbreaking. But then the story changed with them. They were diagnosed with cancer, they got testing, and they shared this information with their family members. So they had stories of children and grandchildren—one woman even had great grandchildren—who were old enough to decide whether or not they wanted to be counseled and some decided to get testing. Many did not carry any of the mutations in the family, and others did. And those who found out that they were a mutation carrier, they had actual things to do. And none of them—none of those family members as we cascade down—have died of cancer.” Summer Lee Cox, Oregon Public Health Division (as cited in Green, 2014).
Read
CDC. (2024, September 25). Family health history and adults. Family Health History. https://www.cdc.gov/family-health-history/family-health-history-and-you/family-health-history-and-adults.html
Alzheimer Society. (2021). Risk factors [Report]. https://alzheimer.ca/sites/default/files/documents/research_risk-factors.pdf
Attribution & References
Except where otherwise noted, content on this page is adapted from:
- What is a genetic condition? by yourgenome, CC BY 4.0 . / 4th main category added.
- How are genetic conditions and genes named? In Help Me Understand Genetics by MedlinePlus, National Library of Medicine, Public Domain with attribution
- 7.5 Mutations Without Detectable Phenotypes In Introduction to Genetics by Natasha Ramroop Singh, Thompson Rivers University, CC BY-NC-SA 4.0
- What does it mean to have a genetic predisposition to a disease? In Help Me Understand Genetics by MedlinePlus, National Library of Medicine, Public Domain with attribution
References
Green, R. F. (2024, April 8). Family health history is a non-modifiable risk factor—or is it?. Genomics and Precision Health Blog – CDC. https://blogs.cdc.gov/genomics/2014/11/13/family-health-history/
National Institute of Neurological Disorders and Stroke (NINDS). (2024, July 19). Mitochondrial disorders. (n.d.). National Institutes of Health (NIH). https://www.ninds.nih.gov/health-information/disorders/mitochondrial-disorders
